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Impaired neural stress resistance and loss of REST in bipolar disorder

Molecular Psychiatry (2023)Cite this article

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Abstract

Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes were also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD.

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Fig. 1: Increased neuronal gene expression and network activity in BD cerebral organoids.
Fig. 2: Abnormal neural development in BD cerebral organoids.
Fig. 3: Oxygen-related stress and mitochondrial function in BD organoids.
Fig. 4: Reduced REST expression and activity in BD cerebral organoids.
Fig. 5: Lithium modulates the development and neural activity of BD cerebral organoids.
Fig. 6: Nuclear REST is reduced in prefrontal cortical neurons in BD.

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Acknowledgements

We thank members of the Yankner laboratory for suggestions and discussion, and the Microscopy Resources (MicRoN) core facility at Harvard Medical School for assistance. Bio-samples and/or data for this publication were obtained from NRGR (supported by cooperative agreement U24 MH068457), a centralized national biorepository for genetic studies of psychiatric disorders. Specifically Study 130: Data and biomaterials were collected as part of an in vivo and in vitro study of simvastatin as a modulator of Wnt/GSK3 signaling, supported by National Institutes of Health grant R21MH093958. This study is based at Massachusetts General Hospital. The Principal Investigators were Roy H. Perlis, M.D., MSc. and Stephen J. Haggarty, Ph.D. Study 163: Study participants were consented and enrolled, data and biomaterials were collected, and cell lines were generated at Massachusetts General Hospital as part of an NIMH/NHGRI Center of Excellence in Genomic Science grant (P50MH106933). The Neurobank PI is Roy Perlis, M.D., MSc; key MGH co-investigators included Hannah Brown, M.D., J. Niels Rosenquist, M.D., Ph.D., Steven Sheridan, Ph.D., and Jennifer Wang, Ph.D. The CEGS co-PIs are Isaac Kohane, M.D., Ph.D., and Roy H. Perlis, M.D., MSc.

Funding

This work was supported by NIH grants RO1MH113279 (to BAY) and RF1-AG048029 (to L-HT), and grants from The Ludwig Family Foundation (to BAY), and the Robert and Renee Belfer Family Foundation (to L-HT).

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Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA

    Katharina Meyer, King-Hwa Ling, Pei-Ling Yeo, Angeliki Spathopoulou, Derek Drake, Jaejoon Choi, Liviu Aron, Jenny M. Tam, George M. Church & Bruce A. Yankner

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA

    Mariana Garcia-Corral, Jenny M. Tam & George M. Church

  3. The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Tak Ko & Li-Huei Tsai

  4. Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, 02115, USA

    Eunjung Alice Lee

  5. Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Roy H. Perlis

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  1. Katharina Meyer
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Contributions

KM, KHL, PLY, LA, and AS performed experiments, and MGC assisted in organoid maintenance and calcium imaging. JC and DD performed bioinformatics analysis. TK and LHT generated new iPSC lines. RHP contributed fibroblasts derived from human subjects for iPSC line generation. EAL, JT, and GMC provided consultation on the study. KM and BAY designed experiments and wrote the manuscript, and BAY directed the study.

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Correspondence to Bruce A. Yankner.

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GMC is a cofounder and senior advisor for GCTherapeutics, Inc., which uses transcription factors for therapeutics. The other authors declare no competing interests.

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Meyer, K., Ling, KH., Yeo, PL. et al. Impaired neural stress resistance and loss of REST in bipolar disorder. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02313-7

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